An injury to a portion of the central nervous system (CNS), i.e., the spinal cord or brain, can not be healed by the same means used to treat tissue types such as bone, muscle, liver, the peripheral nervous system (PNS), and so on. An injured spinal cord, for example, does not heal and recover to become functional again, as other tissue types do. For example, severed axons at the injury site fail to reestablish synaptic connections, resulting in permanent loss of neural activity.
In addition, beginning over the first two weeks after injury, cellular changes are triggered that lead to the formation of scar tissue that acts as a barrier to prevent regeneration. For example, astrocytes, the neuroglial cells which normally provide structural support and protection to the neurons, transform into reactive astrocytes upon injury. These reactive astrocytes accumulate to form the bulk of a scar tissue that forms, which is referred to as a gliosis (or astrogliosis), and, at a later stage, as a glial scar. This gliotic tissue acts as a barrier to the reconnection of remaining uninjured tissue, including axons and neurons, and prevents regeneration of healthy neural tissue. Without regeneration and reconnection, there is no return to functionality.
Other processes that are related to the production of reactive astrocytes and may hamper the recovery are: a) production and dissipation at the injury site of axon-growth inhibiting molecules such as chondroitin-sulfate proteoglycans (CSPGs) and keratan-sulfate proteoglycans (KSPGs); and b) reaction of the immune system, commonly in the form of white blood cells (leukocytes) at the entrance to the injury site.
The barrier formed at the injury site consists of functional barriers or inhibitors, as well as physical barriers. For example, the astrogliosis layer that forms at the injury site, also called the junction (referring to the junction between healthy tissues), prevents the recovery of the set of systems required to restore function including formation of the microvasculature system. With the failure of early vascular recovery, catastrophic vascular collapse ensues leading to tissue cavitation and stroke-like events. The overall failure of repair of the microvasculature induces tissue collapse and a failure to bridge the junction between healthy tissues separated by the glial tissue or glial scar.
One of the only methods currently being researched to solve the problem is irradiation of the injury site with X-rays within two to three weeks after the occurrence of injury, as described, for example, in Kalderon, et al., “Structural Recovery in Lesioned Adult Mammalian Spinal Cord by X-Irradiation of the Lesion Site,” Proc. Natl. Acad. Sci. USA, Vol. 93, pp. 11179-11184 (October 1996), or in Kalderon, at al., “Fractionated Radiation Facilitates Repair and Functional Motor Recovery after Spinal Cord Transection in Rat.” Brain Res. Vol. 904, pp 199-207 (June 2001), both of which are incorporated herein by reference. Although the method has produced some encouraging results in laboratory animals, it has not been shown to produce substantial functional repair of the spinal cord.
Other methods have focused on limiting the functional expression of inhibitors or altering the microenvironment that prevents spontaneous regeneration. Yet others attempt to chemically ablate the inhibitory scar barrier. These methods are limited by the lack of non-invasive methods for delivery of the chemicals/compounds required to produce the effect. These methods also exhibit substantial negative “bystander” effects that are overall deleterious to the repair process, often exacerbating injury.
The central nervous system and other organs may suffer damage from disease as well as from direct injury. For example, diseases affecting the central nervous system such as multiple sclerosis, those associated with mental illness, Parkinson's disease, and epilepsy remain without a cure and have proven especially difficult to treat.
There is a need, therefore, for more successful, safe irradiation methods for assisting functional recovery of a damaged spinal cord or brain, as well as for therapeutic treatment of diseases affecting the central nervous system and other organs.